CN109420182A - 一种集超声/荧光双模态成像及光动力治疗于一体的多功能微泡 - Google Patents
一种集超声/荧光双模态成像及光动力治疗于一体的多功能微泡 Download PDFInfo
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Abstract
本发明涉及一种集超声/荧光双模态成像及光动力治疗于一体的多功能微泡,涉及这类多功能微泡的制备方法及其在肿瘤诊疗方面的用途。集超声/荧光双模态成像及光动力治疗于一体的多功能微泡的结构示意图如图所示,其膜成份包括用于光动力治疗的含光敏剂功能基团的脂质以及常规磷脂,光敏药物的比可根据需要进行调控,载药量大大提高。在超声作用下,该多功能微泡可在肿瘤部位实现定点靶向爆破转变为纳米粒子,极大提高了药物在肿瘤部位的富集及摄取,有效改善光动力抑制肿瘤生长的效果。
Description
技术领域
本发明属于生物医用材料领域,具体涉及一类集超声/荧光双模态成像及光动力治疗于一体的多功能超声微泡,以及其在肿瘤诊疗方面的用途。
背景技术
荧光成像是分子生物学和医学研究极为重要的手段。其中近红外区域(波长600~900nm)生物分子的光吸收最低,而自发荧光最弱,大量的红外光可以穿过组织和皮肤而被检测到。因此,其波长范围被认为是光学成像的“诊断窗”。其独特优势为:①敏感性高;②可通过不同荧光探针的设计实现各种肿瘤的靶向性成像;③可提供实时动态的肿瘤活体成像。但是近红外染料受限于成像深度(不超过1cm),从而影响了在显示深部肿瘤中的应用。
无创性超声成像因其具有便捷、低价和实时成像等无可比拟的优点己被广泛应用于癌症的早期诊断中。超声微泡造影剂是通过引入与组织不同声学特性的材料如气体来改善成像效果的,其既能高质量显示肿瘤形态学信息也能有效反映其生物学特性,显著提高了诊断的准确率。超声成像接收声信号,相比光学成像,大大增加了成像深度。近红外荧光/超声双模态显像,可以取长补短,提供了一种深浅兼顾的诊断肿瘤的新方法。
肿瘤的光动力治疗(phototherapy)发展至今已有逾百年的发展历史,其成本低、组织创伤小、副作用小。光动力疗法的作用机制不同于热消融(利用热效应使组织发生凝固性坏死),它是基于光动力效应的一种治疗方法。当组织内的光敏剂受到特定波长的激光辐照时,光敏剂吸收激光的能量后发生能级跃迁,在回到基态的过程中将部分能量传递给周围的氧,产生活性氧从而对周围组织细胞产生损伤。
理想的光动力治疗应在杀伤肿瘤组织的同时尽可能不损伤周围的正常组织,以保证治疗的有效性和安全性。对于光动力治疗而言,光敏剂是治疗的核心要素,只有在光敏剂存在的部位才能产生光治疗效应而对细胞产生损伤;由于治疗时所用激光能量一般较低,在缺乏光敏剂的情况下单纯的激光辐照对细胞并无杀伤效果。因此光动力治疗的肿瘤靶向性依赖于光敏剂在靶区域的良好聚集。如何实现光敏剂在肿瘤部位的精准聚集是光治疗中面临的一大难题。
随着超声微泡制备技术的迅速发展,超声微泡造影剂除可作为优良的超声成像对比増强剂,在肿瘤诊断方面发挥重要作用外,其在肿瘤的治疗方面也具有巨大的应用潜能。在治疗领域,超声微泡可用作药物、基因和纳米材料等其它治疗物质的控制释放载体,达到靶向输送的目的。但是作为药物载体,首先需要克服超声微泡载药量低的问题。
基于以上考虑,我们开发出了一类集超声/荧光双模态成像及光动力治疗于一体的多功能超声微泡,其特点是将用于光动力治疗的具有光敏剂功能基团的脂质组装到超声造影剂的膜成分中,在超声引导下可在肿瘤部位定点击破微泡,使其转变为纳米粒子,在超声空化作用下,纳米粒子更多的被肿瘤细胞摄取。随后在荧光成像引导下,在肿瘤部位实施光动力治疗。
发明内容
本发明的目的是提供一类集超声/荧光双模态成像及光动力治疗于一体的多功能超声微泡造影剂以及该类微泡的制备方法。
本发明的另一目的是提供上述集超声/荧光双模态成像及光动力治疗于一体的多功能超声微泡造影剂在肿瘤诊疗中的应用。
本发明所述的集超声/荧光双模态成像及光动力治疗于一体的多功能超声微泡造影剂的结构如附图1所示。
本发明中多功能微泡造影剂其特征在于该微泡的壳层是由脂质单分子层构成,其组成同时包括:用于光动力治疗的含有光敏剂功能基团的脂质及各类常规磷脂,微泡内包载惰性气体、液体、固体,含有光敏剂功能基团的脂质和常规磷脂一起自组装成微泡的单分子壳层。
所述的含有光敏剂功能基团的脂质一般指光敏功能基团共价连接到脂质上,其结构一般如下:
其中R1=H或C6~18烷基,R2=C6~18烷基;a,b=2或3;X=N或O,即光敏剂和脂质的连接方式是酯键或酰胺键;所述的含光敏功能基团的脂质经溶胶凝胶过程后在水溶液中能自组装形成脂质体。光敏功能基团包括血卟啉、原卟啉、四苯基卟啉、焦脱镁叶绿酸(pyropheophorbide)、细菌叶绿素、叶绿素a、苯并卟啉衍生物、四氢苯基二氢卟吩、苯并二氢卟吩、萘并二氢卟吩、酞菁或萘酞菁等。所述的超声微泡造影剂由成膜材料包裹气体或者液体构成,所述微泡造影剂的粒径范围为300nm-8um。该微泡可在超声作用下转变为纳米粒子,所述纳米粒子的粒径范围为20nm-700nm。
本发明所述的一种集超声/荧光双模态成像及光动力治疗于一体的多功能微泡的制备方法,包括以下步骤:
1)将一定比例的磷脂、含有光敏剂功能基团的脂质及近红外染料于氯仿(CHCl3)中溶解混合均匀(含有光敏剂功能基团的脂质比例0~20%)。
2)然后通过旋转蒸发仪将氯仿蒸干,使溶解的脂质在旋蒸瓶底部形成脂质薄膜,并置于真空干燥箱中过夜以除去残留的有机溶剂。
3)将生理盐水或PBS水化液加入瓶中,置于60℃水浴超声,直至液体澄清,得到脂质体。
4)将上述所得体系转移至西林瓶中,然后加入丙二醇、甘油作为稳定剂,混匀。
5)往西林瓶中填充惰性内包物质,封口后,使用银汞调和器剧烈震荡45s,分离提纯后得到集超声/荧光双模态成像及光动力治疗于一体的多功能微泡。
在步骤l)中,所述的磷脂包含12~24个碳的碳链长度以及包括磷脂酰胆碱、磷脂酰基乙醇胺、磷脂酸、磷脂酰基甘油和胆固醇,例如1,2-二硬脂酰基-sn-甘油基-3-磷酸胆碱(DSPC)、1,2-二棕榈酰基-sn-甘油基-3-磷脂酰胆碱(DPPC)、1,2-二棕榈酰基-sn-甘油基-3-磷脂酸(DPPA)、二硬脂酰磷脂酰乙醇胺-聚乙二醇2000(DSPE-PEG2000)、二硬脂酰磷脂酰乙醇胺-聚乙二醇2000(DSPE-PEG5000)等。
步骤5)中所述的惰性内包物质包含空气、氮气、二氧化碳、氟碳烃气体,液体选自C5-C12氟碳烃。
本发明中超声/荧光双模态成像及光动力治疗于一体的多功能微泡,其具有光敏剂功能基团的脂质和常规磷脂共同自组装成微泡单分子壳层,光敏药物的比例根据需要进行调控,载药量大大提高;同时,其能够综合荧光和超声两种成像模式,精准定位肿瘤位置;并且在超声作用下实现微泡靶向爆破,增加了光敏剂在肿瘤部位的富集,提高了光动力治疗肿瘤的疗效。
附图说明
图1是本发明所描述的多功能微泡造影剂的结构图;图2是具体实施例1制备得到的多功能微泡的粒径分布图;图3是具体实施例3中微泡造影剂的体外超声造影图像;图4是具体实施例4中多功能微泡造影剂体外在激光照射下产生单线态氧能力的测定;图5是具体实施例5中微泡造影剂在动物肿瘤组织处的超声造影图像;图6是具体实施例6中微泡造影剂在动物肿瘤组织处被超声击破后的荧光成像的图像;图7是具体实施例7中微泡造影剂用于光动力治疗后的动物肿瘤生长曲线。
具体实施方式
通过以下具体实施方式将有助于理解本发明,但并不限制本发明的内容。
实施例1
将15%mol的卟啉脂质(PGL)和50%mol二硬脂酰基磷脂酰胆碱(DSPC)、30%mol胆固醇(cholesterol)、5%mol二硬脂酰基磷脂酰乙醇胺-聚乙二醇2000(DSPE-PEG2000)混溶于2~5mLCHCl3中,然后通过旋转蒸发仪将氯仿蒸干,使溶解的脂质在旋蒸瓶底部形成脂质薄膜,并置于真空干燥箱中过夜以除去残留的有机溶剂。再将1mLPBS水化液加入瓶中,在60℃水浴超声30min,直至获得透明澄清的溶液,即获得PGL脂质体(脂质浓度为1mg/mL)。之后将PGL脂质体溶液转移至西林瓶,加入甘油和丙二醇各100μL混合均匀,然后灌入全氟丙烷气体,密封后用VIALMIX(Lantheus公司,美国)震荡45s,即可获得PGL-MBs,微泡粒径分布如附图2所示。
实施例2
将15%mol的卟啉脂质(PGL)和80%mol二硬脂酰基磷脂酰胆碱(DSPC)、5%mol二硬脂酰基磷脂酰乙醇胺-聚乙二醇2000(DSPE-PEG2000)混溶于2~5mLCHCl3中,然后通过旋转蒸发仪将氯仿蒸干,使溶解的脂质在旋蒸瓶底部形成脂质薄膜,并置于真空干燥箱中过夜以除去残留的有机溶剂。再将1mLPBS水化液加入瓶中,在60℃水浴超声30min,直至获得透明澄清的溶液,即获得PGL脂质体(脂质浓度为1mg/mL)。之后将PGL脂质体溶液转移至西林瓶,加入甘油和丙二醇各100μL混合均匀,然后灌入全氟丙烷气体,密封后用VIALMIX(Lantheus公司,美国)震荡45s,即可获得PGL-MBs。
实施例3
采用临床超声诊断系统DC8(迈瑞,中国)搭配L12-3E线阵探头进行超声检查,将探头放置于模具侧方使声束与样品孔长轴方向垂直,机械指数调节为0.10,聚焦深度设置于样品孔的中心位置。将不同浓度(1×107/ml,5×106/ml,2×106/ml,1×106/ml)的PGL-MBs样品加入琼脂糖模具的圆柱形样品孔中,观察其超声造影效果,之后在超声的实时监控下采用LFUS在模具侧方(线阵探头对侧)进行辐照,观察样品的超声响应性。超声成像的结果如图3所示,PGL-MBs具有超声显影增强的能力,随着微泡浓度的降低,超声造影效果逐渐变弱。
实施例4
以ADPA(disodium salt of 9,10-anthracene dipropionic acid;Sigma)作为单线态氧探针,其最高吸收峰在378nm,与单线态氧发生化学反应后吸收峰吸收会逐渐下降。实验分为四组:(PBS,游离卟啉组,PGL-MBs,PGL-MBs+LFUS(即PGL-NPs)分别检测不同组单线态氧产生情况。实验初始中ADPA溶液在378nm的吸光度均调至2.25,PGL-MBs及PGL-NPs在420nm处的吸光度调至0.65。各个样品用650nm激光照射,每5分钟用紫外-可见光分光光度计测量一次吸收光谱。结果如图4所示,随着激光照射时间延长,ADPA的吸收不断下降,反应了单线态氧产生不断增加。以同样的方法对其他样品进行检测,取ADPA的最大吸收峰378nm的吸光度为纵坐标,以照射时间为横坐标作图,可以看出PBS组的吸光度无明显变化,说明单纯的激光照射并不能产生单线态氧。而PGL-MBs+LFUS及PGL-MBs组的单线态氧产生明显高于游离卟啉组,可能是因为游离卟啉在水溶液中不能良好地分散,而使单线态氧产生效率减低。PGL-MBs+LFUS组的单线态氧略高于PGL-MBs组,推测可能与检测过程中PGL-MBs组的微泡在水溶液中上浮使溶液中粒子浓度降低有关,导致检测结果出现偏差。
实施例5
以10%水合氯醛溶液注射于腹腔将PC3荷瘤裸鼠麻醉,再经尾静脉注射100μLPGL-MBs(磷脂浓度为1mg/mL)溶液,利用临床超声诊断系统DC8(迈瑞)在谐波成像模式下对肿瘤局部进行成像,并录制视频;在超声造影的引导下对肿瘤局部的微泡进行LFUS辐照(每辐照6s暂停6s),观察微泡击破及再灌注情况,当无血管内无明显微泡时停止LFUS辐照。超声成像的结果如图5所示,PC3荷瘤裸鼠经尾静脉注射100uLPGL-MBs后,谐波成像模式下可清晰显示肿瘤的血供情况,可以看到微泡在肿瘤内灌注并逐渐填充整个肿瘤组织,说明PGL-MBs有良好的超声造影效果。
实施例6
为了评估实施例1-2中获得的多功能微泡在体内对肿瘤进行荧光成像的能力,对接种了皮下PC3肿瘤的小白鼠进行荧光成像。微泡的浓度为108/mL,按照1mL/kg的浓度尾静脉注射到小白鼠体内,紧接着注射100μL生理盐水。在超声成像引导下进行高能量超声辐照肿瘤部位击碎微泡(1.03MHz,50%duty,1W/cm2,3min),利用IVIS小动物荧光活体成像系统(CaliperLifeSciences)实时监测PGL的分布情况。在微泡注射前(pre)及LFUS辐照完毕后不同时间点(如30min、1h、2h、6h、24h)分别对小鼠进行荧光活体成像,观察PGL分布情况以确定最佳治疗时间点。成像结果见图6可看出,相比于单纯PGL-MBs注射组,PGL-MBs+LFUS组可在肿瘤局部看到明显的PGL聚集,且在6h内时均保持较高的荧光强度,24h后肿瘤局部荧光强度减低,但是荧光信号仍强于其他部位。
实施例7
将接种了皮下PC3肿瘤的裸鼠分为8组,分别予以不同处理(表1),每天用游标卡尺记录皮下肿瘤的大小。从治疗后当天起每天记录各组肿瘤体积,到第10天设置为治疗终点(因大部分裸鼠肿瘤体积超过2000mm3)。附图7中肿瘤生长曲线可见,PGL-MBs+LFUS+Laser组的肿瘤生长完全被抑制,肿瘤体积未见增大。统计分析显示自第3天起PGLMBs+LFUS+Laser组与其余各组间肿瘤体积差异有统计学意义(P<0.05),至第10天时该组肿瘤体积为107±73mm,而其余各组肿瘤体积均数均接近或超过2000mm3,且各组之间的均数差异无统计学意义。
表1 动物实验分组及处理
备注:LFUS辐照时间为3min(此时绝大部分PGL-MBs已击破);
激光处理为650nm激光器(200mW/cm2)辐照30min。
Claims (9)
1.一种用于集超声/荧光双模态成像光动力治疗于一体的多功能微泡,其特征在于该微泡的壳层是由脂质单分子层构成,其组成同时包括:用于光动力治疗的含有光敏功能基团的脂质及各类常规磷脂,微泡内包载惰性气体或液体,含有光敏剂功能基团的脂质可以和常规磷脂在水溶液中共同自组装形成微泡。
2.根据权利要求1所述的一种集超声/荧光双模态成像及光动力治疗于一体的多功能微泡,其特征在于该微泡可在超声作用下转变为纳米粒子,所述纳米粒子的粒径范围为20nm-700nm。
3.根据权利要求1所述的一种集超声/荧光双模态成像及光动力治疗于一体的多功能微泡,其特征在于光敏功能基团共价连接到脂质上,其结构一般如下:
其中R1=H或C6~18烷基,R2=C6~18烷基;a,b=2或3;X=N或O,即光敏剂和脂质的连接方式是酯键或酰胺键;所述的含光敏功能基团的脂质经溶胶凝胶过程后在水溶液中能自组装形成脂质体。
4.根据权利要求3所述的光敏功能基团包括血卟啉、原卟啉、四苯基卟啉、焦脱镁叶绿酸(pyropheophorbide)、细菌叶绿素、叶绿素a、苯并卟啉衍生物、四氢苯基二氢卟吩、苯并二氢卟吩、萘并二氢卟吩、酞菁或萘酞菁等。
5.根据权利要求1所述的一种集超声/荧光双模态成像及光动力治疗于一体的多功能微泡,其特征在于所述的超声造影剂由成膜材料包裹气体或液体所构成,所述微泡造影剂的粒径范围为300nm-8um。
6.如权利要求1所述的一种集超声/荧光双模态成像及光动力治疗于一体的多功能微泡的制备方法,其特征在于包括以下步骤:
1)将一定比例的磷脂、含有光敏剂功能基团的脂质及近红外染料于氯仿(CHCl3)中溶解混合均匀(含有光敏剂功能基团的脂质比例0~20%)。
2)然后通过旋转蒸发仪将氯仿蒸干,使溶解的脂质在旋蒸瓶底部形成脂质薄膜,并置于真空干燥箱中过夜以除去残留的有机溶剂。
3)将生理盐水或PBS水化液加入瓶中,置于60℃水浴超声,直至液体澄清,得到脂质体。
4)将上述所得体系转移至西林瓶中,然后加入丙二醇、甘油作为稳定剂,混匀。
5)往西林瓶中填充惰性内包物质,封口后,使用银汞调和器剧烈震荡45s,分离提纯后得到集超声/荧光双模态成像及光动力治疗于一体的多功能微泡。
7.根据权利要求6所述的常规磷脂包含12~24个碳的碳链长度以及包括磷脂酰胆碱、磷脂酰基乙醇胺、磷脂酸和磷脂酰基甘油,例如1,2-二硬脂酰基-sn-甘油基-3-磷酸胆碱(DSPC)、1,2-二棕榈酰基-sn-甘油基-3-磷脂酰胆碱(DPPC)、1,2-二棕榈酰基-sn-甘油基-3-磷脂酸(DPPA)、二硬脂酰磷脂酰乙醇胺-聚乙二醇2000(DSPE-PEG2000)、二硬脂酰磷脂酰乙醇胺-聚乙二醇2000(DSPE-PEG5000)等。
8.根据权利要求6的步骤5)所述的惰性内包物质包含空气、氮气、二氧化碳、氟碳烃气体,液体选自C5-C12氟碳烃。
9.根据权利要求1所述的一种集超声/荧光双模态成像及光动力治疗于一体的多功能微泡,其特征在于该微泡可用于肿瘤的诊断和治疗。
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